Novel Sortase A (SrtA) inhibitors interfere with the formation of staphylococcal biofilms

Staphylococcus aureus, due to its wide arsenal of virulence factors, is a very versatile pathogen responsible for a wide variety of infectious diseases. The virulence factors include the cell-wall associated proteins that have a direct role in the first stage of pathogenesis. The Sortase A (SrtA) transpeptidase is responsible for covalent anchoring to the cell wall of various surface proteins and it is considered a good target to design new antivirulence agents. In this study, we report the identification of an inhibitor of SrtA afforded from the random screening of a small molecular library of around 150 synthetic compounds, through a high throughput assay by using the standard Dabcyl-QALPETGEE-Edans fluorescence resonance energy transfer (FRET)-peptide substrate for measurement of enzyme activity. Such hit compound showed an IC50 value of 80µM. A group of derivatives of the hit compound has been obtained and evaluated for their activity as SrtA inhibitors. The efficacy of the most interesting SrtA inhibitors needs to be evaluated by in vivo models of infection, but we used a simple methodology in vitro, such as inhibition of biofilm formation, for a preliminary assessment of antivirulence properties of some of these novel inhibitors of SrtA. An interesting correlation between inhibition of SrtA and interference with the formation of staphylococcal biofilms has been observed in many cases especially at a concentration equal or more than IC50 determined as SrtA inhibitors.